Aminoalkanoyl-halo-toluidides



United States Patent-Q 2,823,209 AMINOALKANOYL-HALO-TOLUIDIDES Henry Martin, Zurich, Switzerland, assignor to Cilag Lim--' ited, Schalfhausen, Switzerland, a Swiss company No Drawing. Application February24, .1953 Serial No. 338,601 Claims priority, application Switzerland February 25, 1952 4 Claims. (Cl. 260326.3)

This invention relates to new halogen-containing amino fatty acid anilides, their acid addition and quaternary ammonium salts and their production.

The invention provides new chemical compounds being amino fatty acid 2-halogeno-6-methyl anilides of the formula Halogeno R CH3 wherein halogend signifies a chlorine or bromine atom, R is a hydrogen atom or a lower alkyl radical, Acyl is the radical of a lower straight or branched fatty acid and.

agent. This quaternary compound has not the slightest v local anaesthetic effect; nor has the intermediate product N,N-dimethyl-amino acetic The 0-, mand p-iodo anilides of diethylamino acetic acid acid-3,4-dichloro-anilide.

also have no anaesthetic efiect (Arkiv for Kemi, Mineralogi o. Geologi, vol. 22A, No. 18, page 19). It was therefore surprising to find that, unlike the above-mentioned halogen-containing dialkyl amino acetic acid ani- 2,823,209 Patented Feb. 11, 1958 "ice wherein R has the above-defined meaning, or aasalt there'- of, for example, 2-chloro-6-methylaniline or one of its N-alkyl derivatives or a hydrochloride of such a com- ..pound, is treated with a compound, yielding the .amino fatty acid radical.

In some cases it 1s easier to proceed step by step;and

to employ in the first insteincea-compound yielding the halogeno fatty acid radical ,Injthis'. case therhalogeno. fatty acid halogeno-methylanilide first-obtained isreacted with an amine to obtainthe desired amino fatty acid. 101112 idide." f

Other methods are also. available for. producing .the .7

new halogen-containing N-subs'tituted amino fatty acid toluidides: Amino fatty acid halogeno-methyleanilides unsubstituted at the aliphatic nitrogen maybe alkylated or aralkylated in known manner to form N,N-substituted.

amino fatty acid halogeno-methylanilides. Or the corresponding reactive, unsaturated-fatty acid halogenorrnethylanilides, for example the corresponding amide of acrylic acid, are reacted with secondary aminesinthe presence of catalysts .to form ,fi-N,l-I-dialkyl-aminov fatty acid 2-halogeno-6-methyl-anilides.' 2-halogeno-6-methyl anilines suitable for the reactioninclude 2-chloro-6-methyl aniline, 2-bromo-6-methyl-aniline, their N-alkyl derivatives and their salts, for example the hydrochlorides.

Compounds yielding the fatty acid radical -X-Acylof the general formula include: dialkylamino acetic acids and their reactive derivatives, for example N-allyl-amino acetic acids, p-(N,N-diethylamino)-propionic acid, lower alkyl esters of.N,N-dibenzylamino aceticacid, dibenzylamino acetic acid amide, andtalso reactivehalogeno fatty acid derivatives such as chloro-acetic acid, chloro-acetic acid anhydride, chloro-acetyl chloride, a-chloro-propionic 1 acid chloride, a-bromo-propionic acid bromide, p-bromopropionic. acid bromide, a,fl-dibromo-propionylchloride, a-bromo-butyric acid bromide and reactive unsaturated acids such as acrylic acid and methacrylic acid andtheir reactive derivatives such as methacrylic acid chloride.

In general the reaction with the aromatic base .occursin a solvent such as aqueous acetone,- ethyl acetate, dioxane or chloroform. Depending on the circumstances and the reactants, the reaction may also be carried out in the molten state without a solvent, as for example may the.

reaction of 3-chloro-2-toluidide hydrochloride with chloro-acetic acid amide.

lides, the 2-halogeno-6-methyl-anilides of N-substituted amino fatty acids show very remarkable local anaesthetic properties. Although it is known that certain amino fatty acid xylidides and mesidides have an anaesthetic effect, the o-toluidides of aliphatic amino fatty acids, for ex.- ample dimethyl amino acetic acid N-methyl-o-toluidide and N-rnorpholino acetic acid o-toluidide have. no,.or at least no perceptible effect.

The new compounds of the invention are distinguished by their excellent properties. They have a low toxicity and an outstanding anaesthetic effect. They can, if desired, be mixed with vasoconstrictor agents such as adren- 1 aline. Their aqueous acid solutions are stable and may be applied without affecting the tissues. Unlike the difficultly accessible xylidides of the amine fatty acids, the new Z-halogeno-G-methyl anilides may easily be produced synthetically in any desired quantity and may be obtained without a time-consuming purification of the starting material.

The new compound can be produced as follows: A compound of the formula halogeno NH-R l CH3 Bases which are suitable for the reaction with the halogeno fatty acid toluididesiinclude: ammonia, primary .or i

secondary amines, for example mono -n-butyl amine, allyl amine, dimethyl amine, diethyl amine, morpholine, piperidine, a-methyl piperidine, pyrrolidine, cyclohexyl amine and benzyl methyl amine. Derivatives alkylated at the aromatic nitrogen mayv furthermore be prepared by alkylating an amino fatty acid halogeno-methyl-anilide of the formula halogeno which is preferably caused to react in form of an N-alkali metal salt halogeno If-Acyl-X H CH:

Preferred alkylating agents are the esters of alkanols with strong inorganic acids, for example hydrohalide, sulphuric acid, alkyland aryl-sulphonic acid esters.

The new compounds of the invention may beused as local anaesthetics in theform of their saltswith-inorga-Hi;

production of the new compounds: 7

Example 1 141 parts by weight of 2-chloro-6-methylaniline are dissolved in 250 parts of acetone, a solution of 205 parts of crystallised sodium acetate in 300 parts of water is added and then 142 parts of chloro acetyl chloride at a temperature of 38-55 C. are added drop by drop with stirring in the course of 3 hours. After some time the chloro-acetic acid-2-chloro-6-methylanilide starts separating. After stirring for one hour 200 parts of water are added and the mixture cooled with continued stirring. The condensation product is filtered 017? with suction, washed with water and dried in vacuo. The crude product sinters at 123 melting point is 140141 C.

109 parts of chloro-acetic acid 2-chloro-6-methyl-anilide thus obtained are suspended in 180 parts of'ethanol and 110 parts of diethylamine are added. The tempera ture rises to 34 C. and a great part of the reaction 'mix-' ture dissolves. After half an hour the whole is dissolved. First it is stirred for 4 hours at room temperature, then for three hours at 4550 C. and finally for 4 hours at Yield 189 parts C. and meltsat.139.5 140.5 C. When recrystallised from diluted alcohol the 6575 C. A sample tested with dilute hydrochloric acid gives a clear solution. Afterwards the alcohol'and the excess diethylamine are distilled off with steam, and after cooling the remaining oil is taken up in ether. After drying the etheral solution and separating the solvent, an oil remains in a yield of 117 parts. The reaction with diethylamine may also take place in benzene.

The N,N-diethylamino-acetic acid 2-chloro-6-methylagglide thus obtained boils under 0.1 mm. Hg at 129- 1 C.

The hydrochloride of the base, when recrystallised from acetonitrile, melts at 154l55 C.

In a similar manner the N,N-dimethylamino-acetic acid 2-chloro-6-methylanilide may be produced; the free base distils under 0.2 mm. Hg at 128132 C. and melts at 7173 C. The hydrochloride melts at 231234 C.

N-morpholino-acetic acid 2-chloro-6-methylanilide obtamed in an analogous manner melts at 119.5120.5 C

when recrystallised from methyl isobutyl ketone; the corresponding hydrochloride melts at 210.5213.5 C.

N-piperidino-acetic acid 2-chloro-6-methylanilide melts A at 107108 C.; the hydrochloride melts at 172173 C.

N-fi-methylpiperidino-acetic acid 2-chloro-6-methylanilide melts at 97-99" C.; the hydrochloride melts at 177 180 C.

Instead of 2-chloro-methylaniline, 2-bromo-6-methyl-" aniline may be used; by using aor B-chloro-propionyl chloride instead of chloro-acetyl chloride and reacting the obtained aor B-chloro-propionic acid 2-chloro-6- methylanilide which is respectively obtained with the aforementioned amines, the analogous aor fi-amino propionic acid 2-chloro-6-methylanilide is obtained respectively.

Example 2 filtrate is treated with solid sodium chloride Thereupon the hydrochloride of amino-acetic acid 2-chloro-6-methylanilide precipitates in beautiful crystals. It is recovered,

dried and recrystallised from alcohol. It melts at 290 C. with decomposition.

The amino-acetic acid 2-chloro-6-methylanilide is then methylated with aqueous formaldehyde solution and formic acid or with dimethyl sulphate in a benzene solution, yielding N,N-dimethylamino-acetic acid 2-chloro-6- methylanilide, B. P. l29-130 C./0.1 mm. Hg.

Example 3 141 parts of 2-chloro-6-methylaniline are dissolved in absolute ether and reacted with stirring at 10-20 C. with 52 parts of methacrylic acid chloride for 10 minutes. The temperature slowly rises to. 38 C. and a thick mass is slowly formed. After standing over night the reaction mixture is filtered with suction, the residue is washed with ether and the ether is washed in turn with dilute hydrochloric acid and 2 N .sodium hydroxide. After drying and separating the solvent, an oil is obtained which becomes solid at about C. The resultant methacrylic acid-2-chloro-6-methylanilide is recrystallised from tetrachloro methane and petroleum ether in beautifui leaflets of melting point 102 C.

20 parts of this acetic acid amide are heated for 16 hours under reflux with an excess of diethylamine in the presence of a few drops of trimethyl benzyl ammonium hydroxide on the water bath and then treated with dilute hydrochloric acid. The liquid is filtered from a little undissolved material and made slightly alkaline, and the excess diethylamine is distilled off with steam. The resultant B-N,Nrdiethylamino-isobutyric acid 2-chloro-6- methylanilide is filtered, dried and distilled. B. P. l39 C./0.1 mm. Hg.

Acrylic acid 2-chloro6-methylanilide on reaction with diethylamine gives 'y- I,N-diethylamino-p ropionic acid 2-chloro-6-methylanilide and on'reaction with dimethylamine gives 'y-N,N-dimethylamino-propionic acid 2-chloro-6-rnethylanilide, the hydrochloride of which melts at 78.579.5'C.

Example 4 1 mol. of 2-chloro-6-methylaniline hydrochloride is thoroughly mixed with 1 mol of chloro-acetarnide and heated on an oil bath up to l25 130 C. The reaction mixture becomes solid after first beginning to melt. After one hour it is taken up in xylene and treated with a little charcoal. From the filtered solution, chloro-acetic acid 2-chloro-6-methylanilide of melting point -141 C. crystallises. It is reacted with pyrrolidine as described in Example 1, forming N-pyrrolidino-acetic acid 2-chloro-6- methylanilide melting at 84-85 C., its hydrochloride melting at 194-196 C.

Example 5 By reacting chloro-acetic acid 2-chloro-6-methylanilide with Z-methyl-piperidine in excess, 2-methylpiperidinoacetic acid 2-chloro-6-methylanilide is obtained melting at 97-98 C., its hydrochloride melting at l77-178 C.

Example 6 23 girls. of chloro-acetic acid N-methyl-Z-chloro-G- methylanilide (obtained from 2-chloro-6-methyl-N- methylaniline and chloro-acetic acid chloride by the above 7 described process) are heated under reflux for 15 hours with stirring with 20 gms. of pyrrolidine in 40 cc. of absolute ethanol. Afterwards the alcohol and surplus pyrrolidine are distilled off with steam, the remaining aqueous solution is saturated with sodium chloride and the oil which separates is taken up in ether. The other is dried with sodium sulphate and evaporated, and the residue is distilled in vacuo. In this way 17 gms. of pyrrolidino-acetic acid N-methyl-2-chloro 6 methylanilide are obtained, boiling under 0.05 mm. Hg at 123- 125 C. The new com-pound is easily soluble in dilute mineral acid. An aqueous solution of the hydrochloride shows a pH of 6.6.

Example 7 In an analogous manner to that described in Example 1, 23 gms. of chloro-acetic acid N-methyl-2-chloro-6-rnethy1- anilide are reacted with 20 gms. of diethylamine to give 22 gms. of N,N-diethylamino-acetic acid N-methyl-2- chloro-6-methylanilide boiling under 0.35 mm. Hg. at l27-130 C. An aqueous solution of the hydrochloride shows a pH of 6.6. The following are obtained in an analogous manner to that described in the foregoing examples: N,N-diethylamino-acetic acid N-ethy1-2-chloro- 6-methy1anilide, N,N-diethylamino-acetic acid N-propyl- 2-chloro-6-methylanilide, piperidino-acetic acid N-methy1-2-chloro-6-methylani1ide, a methylpiperidino acetic acid N'-methyl-2-ch1oro-6-methylanilide, morpholinoacetic acid N'-methy1-2-chloro-fi-methylanilide, as well as the corresponding 2-bromo compounds.

3. The new chemical compound of the formula 6 4. New chemical compound selected from the group consisting of amino fatty acid-2-halogeno-6-methylanilides and hydrochloric acid addition salts thereof, said amino fatty acid-Z-halogeno-G-methyl anilides having the formula halogeno CH3 wherein halogeno is an atom selected from the group consisting of chlorine and bromine, R is a member selected from the group consisting of -OH CH -CH and and X is a member selected from the group consisting of a (di-lower alkyl)-amino group and a pyrrolidino group.

References Cited in the file of this patent UNITED STATES PATENTS 2,139,190 Iselin et a1. Dec. 6, 1938 2,343,071 Martin et a1 Feb. 29, 1944 2,441,498 Loefgren et a1 May 11, 1948 OTHER REFERENCES Loefgren: Ar Foer Kemi, Mineralogi och Geologic, vol. 22A, No. 18, pp. 1-30 (1946),

Loefgren et al.: Svensk Kern Ti vol. 58, pp. 206- 231 (1946). 

3. THE NEW CHEMICAL COMPOUND OF THE FORMULA
 4. NEW CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF AMINO FATTY ACID-2-HALOGENO-6-METHYLANILIDES AND HYDROCHLORIC ACID ADDITION SALTS THEREOF, SAID AMINO FATTY ACID-2-HALOGENO-6-METHYL ANILIDES HAVING THE FORMULA 